Hopeful Peter Attia Podcast with John Kastelein

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circular
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Hopeful Peter Attia Podcast with John Kastelein

Post by circular »

#255 ‒ Latest therapeutics in CVD, APOE’s role in Alzheimer’s disease and CVD, familial hypercholesterolemia, and more | John Kastelein, M.D., Ph.D.

This is such an interesting and hopeful podcast for us. I skipped way ahead past the first part about familial cholesterolemia to hear about Apoe4, and now I'm going to listen again to the entire thing so better grasp it all and can put the ApoE4 information into more context.

The short of it is that the most recent CETP inhibitor being researched is blowing prior versions out of the water in terms of efficacy, and the safety, so far, is still good. They discuss how it may reverse ApoE4's issues with respect to cholesterol, and at least to some extent also inflammation, for a very cheap, low dose pill. I think, although I'm hardly educated enough in this area to have any opinion, they pretty much put to rest the idea that high HDL offsets high LDL. I also now find it hard to believe that ApoE4s need higher LDL to compensate for the dysfunctional way that ApoE4 mismanages LDL metabolism.

I couldn't find this posted yet in the forum, so hopefully it's not a repeat.

Since I don't know this landscape or Peter Attia's perspectives well, I'd love to hear others' comments after listening.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Hopeful Peter Attia Podcast with John Kastelein

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I'm new to this forum, but longtime Drive listener. I concur with you that this podcast is an exciting one. So, thanks for posting here. As e3/e4 I'm also interested in others thoughts & take-aways. Upon re-listening to parts of this episode today I was inspired to try to get more up to date news on the CETP inhibitor discussed (obicetrapib). I found the email list https://ir.newamsterdampharma.com/share ... ail-alerts may be a source of upcoming news on the trials happening with it.
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Re: Hopeful Peter Attia Podcast with John Kastelein

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circular wrote: Sat Jul 08, 2023 3:32 pm #255 ‒ Latest therapeutics in CVD, APOE’s role in Alzheimer’s disease and CVD, familial hypercholesterolemia, and more | John Kastelein, M.D., Ph.D....
The short of it is that the most recent CETP inhibitor being researched is blowing prior versions out of the water in terms of efficacy, and the safety, so far, is still good. They discuss how it may reverse ApoE4's issues with respect to cholesterol, and at least to some extent also inflammation, for a very cheap, low dose pill. I think, although I'm hardly educated enough in this area to have any opinion, they pretty much put to rest the idea that high HDL offsets high LDL. I also now find it hard to believe that ApoE4s need higher LDL to compensate for the dysfunctional way that ApoE4 mismanages LDL metabolism.

I couldn't find this posted yet in the forum, so hopefully it's not a repeat.

Since I don't know this landscape or Peter Attia's perspectives well, I'd love to hear others' comments after listening.
springmeyer wrote: Wed Nov 22, 2023 3:19 pm I'm new to this forum, but longtime Drive listener. I concur with you that this podcast is an exciting one. So, thanks for posting here. As e3/e4 I'm also interested in others thoughts & take-aways. Upon re-listening to parts of this episode today I was inspired to try to get more up to date news on the CETP inhibitor discussed (obicetrapib). I found the email list https://ir.newamsterdampharma.com/share ... ail-alerts may be a source of upcoming news on the trials happening with it.
Welcome, springmeyer!

We're glad to have you as a new forum member who found the post from our long-time member "circular". I've "quoted" circular by clicking on the quote icon in the upper right corner of their post, so they get an email notification of your response. It's a handy, if somewhat clunky, way of keeping dialogue going.

I'm way behind on Peter Attia's podcasts, so appreciate you both posting. I found the abstract from an August 2022 article in the respected journal Nature and added some emphasis in boldl:
Global guidelines for the management of high-cardiovascular-risk patients include aggressive goals for low-density lipoprotein cholesterol (LDL-C). Statin therapy alone is often insufficient to reach goals and nonstatin options have limitations. Here, we tested the lipid-lowering effects of the cholesteryl ester transfer protein (CETP) inhibitor drug obicetrapib in a randomized, double-blind, placebo-controlled trial in dyslipidaemic patients (n = 120, median LDL-C 88 mg dl−1) with background high-intensity statin treatment (NCT04753606). Over the course of 8 weeks, treatment with 5 mg or 10 mg obicetrapib resulted in a significant decrease as compared with placebo in median LDL-C concentration (by up to 51%; P < 0.0001), the primary trial outcome. As compared with placebo, obicetrapib treatment also significantly (P < 0.0001) decreased apolipoprotein B (by up to 30%) and non-high-density lipoprotein cholesterol (non-HDL-C) concentration (by up to 44%), and significantly (P < 0.0001) increased HDL-C concentration (by up to 165%; the secondary trial outcomes) and had an acceptable safety profile. These results support the potential of obicetrapib to address an unmet medical need for high-cardiovascular-risk patients.
Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial

It seems likely that they will get investor or NIH funding for a large Phase 3 trial based on those results.

Although you found Circ's post apparently easily, here are some other resources you may want to check out:

The Primer is written by Stavia, a practicing M.D. with ApoE4/4. It's a great place to see a wide range of strategies, and in her Appeindix she offers suggestions for biomarkers to track.

Our Stories is a place where you can view the experiences and often the solutions members have shared.

How to get the Most out of the Website offers screenshots and sections on almost any topic you'd be interested in. It's part of our Wiki whose main index page shows the range of interests we have.
And if you're wondering if someone has posted on a topic, try the text box labeled "Search" right under your user name and enter those terms.

Hope you find the forum useful, and share more great research and your own experiences with us!

Nancy
4/4 and still an optimist!
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Re: Hopeful Peter Attia Podcast with John Kastelein

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springmeyer wrote: Wed Nov 22, 2023 3:19 pm I'm new to this forum, but longtime Drive listener. I concur with you that this podcast is an exciting one. So, thanks for posting here. As e3/e4 I'm also interested in others thoughts & take-aways. Upon re-listening to parts of this episode today I was inspired to try to get more up to date news on the CETP inhibitor discussed (obicetrapib). I found the email list https://ir.newamsterdampharma.com/share ... ail-alerts may be a source of upcoming news on the trials happening with it.
Hi Springmeyer, Thanks for finding this. I never did get around to listening again, so I’ve bumped it back up in my pile. I also signed up for news alerts (thanks for the link), and found a 9/21/23 item in their news of interest to us:
NewAmsterdam Pharma Announces Initial Data from Phase 2a Clinical Trial Evaluating Obicetrapib in Patients with Early Alzheimer’s Disease Who Carry an ApoE4 Mutation

-- Observed reductions of 11% and 12% in 24- and 27-hydroxycholesterol in cerebrospinal fluid (“CSF”), respectively, indicating potential improvement of cholesterol metabolism in the brain --
-- Observed 8% increase in Aβ42/40 ratio, a key biomarker of AD risk, suggesting improvement in disease pathology --
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Hopeful Peter Attia Podcast with John Kastelein

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NF52 wrote: Wed Nov 22, 2023 5:59 pm
Thanks for linking me in Nancy! I’d long since forgotten about this so will make a another attempt to listen again. See my reply to springmeyer above :)
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Hopeful Peter Attia Podcast with John Kastelein

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Beginning at 1:41:30 https://youtu.be/Jduj5SL5FNs?si=mB5cTOUKGc9T-jk7&t=6090

John Kastelein, MD PhD

Worth listening to for anyone interested in the functionality (or lack thereof) of ApoE4. Notes attached.
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Re: Hopeful Peter Attia Podcast with John Kastelein

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circular wrote: Wed Nov 22, 2023 6:21 pm found a 9/21/23 item in their news of interest to us:
NewAmsterdam Pharma Announces Initial Data from Phase 2a Clinical Trial Evaluating Obicetrapib in Patients with Early Alzheimer’s Disease Who Carry an ApoE4 Mutation

-- Observed reductions of 11% and 12% in 24- and 27-hydroxycholesterol in cerebrospinal fluid (“CSF”), respectively, indicating potential improvement of cholesterol metabolism in the brain --
-- Observed 8% increase in Aβ42/40 ratio, a key biomarker of AD risk, suggesting improvement in disease pathology --
Thank you for that reference! It is unclear to me what that trial is named. The 21 September 2023 Press Release lists "five of the Company’s Phase 2 trials, ROSE2, TULIP, ROSE, OCEAN, and TA-8995-203," and "two Phase 3 pivotal trials, BROADWAY and BROOKLYN," and "Phase 3 PREVAIL."
aphorist wrote: Sun Apr 14, 2024 4:20 am Beginning at 1:41:30 https://youtu.be/Jduj5SL5FNs?si=mB5cTOUKGc9T-jk7&t=6090

John Kastelein, MD PhD

Worth listening to for anyone interested in the functionality (or lack thereof) of ApoE4. Notes attached.
Thank you for the video link with timing cue and the attached notes (though the embedded hyperlinks do not work for me)! The discussion mentioned "the Alzheimer's trial" being an unnamed fourth trial that is not PREVAIL, which according to the 9 April 2024 Press Release is among four trials of that series, so perhaps it's TANDEM?
We expect data from PREVAIL will complement results from our ongoing pivotal Phase 3 trials, BROADWAY, BROOKLYN and TANDEM, and further support obicetrapib’s clinical profile as a well-tolerated and potentially highly effective option for treating hypercholesterolemia and preventing serious cardiovascular disease, if approved.
With the PREVAIL CVOT enrollment target met and topline data from BROOKLYN and BROADWAY expected in the third and fourth quarter of 2024, respectively, and TANDEM in the first quarter of 2025, we look forward to executing our ongoing programs and to sharing our first pivotal datasets in the months ahead.
Phase 2, Phase 2a, Phase 3... I can't seem to work out which trial is doing what and when, but I'm eager for results! According to Michael Davidson, MD & CEO New Amsterdam Pharma:
We are currently in the mid stages of Phase 3 trials, aiming to complete them in the second half of 2024. Our goal is to launch the drug after the completion of a cardiovascular outcome trial which we expect to be completed in late 2026.
Meanwhile, this insightful paper referenced in the Hypertriglyceridemia section of our wiki seems supportive: APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease:
  • ApoE Structure and Function
  • The Importance of ApoE Recycling to Cellular Bioenergetics
  • Genetic Regulation APOE Expression Through the PPAR-LXR-ApoE System
  • Effect of APOE4 on Triglyceride and Cholesterol Metabolism
  • APOE4 and Adipocytes
  • APOE Genotype and Sex
  • APOE Genotype and the Immune System
  • APOE Genotype and the Vascular System
  • APOE Genotype and the Brain
  • APOE Genotype and the Chromosome 19q13 Gene Cluster
  • Ethnic Differences in the Associations of APOE4 With AD Risk
  • The Response of APOE4 Carriers to Dietary and Lifestyle Interventions
  • The Resistance of APOE4 Carriers to Drugs Targeting the PPAR-LXR/RXR-APOE System
  • APOE4 Brain Fuel Preferences and Response to Diet
  • The Cognitive Vulnerability of Older APOE4 Carriers to Weight Loss
  • A Role for Omega-3 Enriched Diets in APOE4 Carriers
Excerpts of particular relevance to this thread:
One of the characteristics of apoE4 is its lower recycling capacity, which likely results from its greater affinity for lipid binding. Indeed, HDL induced cellular recycling of apoE4 is much weaker than other apoE isoforms. This property decreases cholesterol efflux (Heeren et al., 2004) and enriches the cell membrane with cholesterol.
...
Recycling of apoE appears to depend on the expression of the LDL receptor (LDLr; Fan et al., 2011) and the activity of ATP binding cassette 1 (ABCA1; Rawat et al., 2019). ABCA1 functions to lipidate apoA-1 and apoE, forming small nascent HDL particles. While ABCA1 activity is not required for apoE recycling (Braun et al., 2006), it can indirectly enhance apoE recycling through mediating the formation of smaller HDL particles (HDL3) which directly stimulate apoE secretion and recycling.
...
Reduced recycling of apoE4 also affects cellular cholesterol metabolism. ApoE4 traps ABCA1 in endosomes away from the cell surface (Rawat et al., 2019). Reduced ABCA1 activity results in lower cholesterol efflux to HDL and redistributes cholesterol to cell membranes.
...
The mechanism for hypertriglyceridemia in APOE4 may involve its stronger binding to VLDL, which decreases lipoprotein lipase mediated lipolysis (Li et al., 2013). A major mechanism for hypercholesterolemia with APOE4 is through the sequestration of apoE proteins on the hepatic cell surface.
-Jim
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Re: Hopeful Peter Attia Podcast with John Kastelein

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OfficeSpace wrote: Sat Apr 20, 2024 6:35 am Thank you for the video link with timing cue and the attached notes (though the embedded hyperlinks do not work for me)!
See if this fixes it.
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Re: Hopeful Peter Attia Podcast with John Kastelein

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aphorist wrote: Sun Apr 21, 2024 12:54 pm See if this fixes it.
Thank you! That is most helpful, as I could access only the first part here.

"John will have data on Alzheimer's Disease in the summer and is really thrilled to understand what's happening in the brain." :idea:
-Jim
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Re: Hopeful Peter Attia Podcast with John Kastelein

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Are there any studies linking 2 copies (GG) of CETP being protective against CVD? Would the inhibitors be unnecessary for someone with this genotype? I have quite high LDL (280, and APOB of 160) , high HDL (100 ish) and low triglycerides (eat low carb mostly) and have 0 CAC and CTA scores at 61. I Am apoe 3/4. The LMHR cohort would suggest my lack of CVD is likely due to my diet, but I wonder if genetics is playing a role. I am not always ketogenic like LMHR . I looked at the research on this years ago but recall contradictory conclusions.
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